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Diabetic Nephropathy: Prevention and Management
Review Article
DIABETIC NEPHROPATHY: PREVENTION AND MANAGEMENT Sai Prasad Sahoo*, Sandeep Mandal** and Sanjiv Jasuja*** *Registrar, **Clinical Associate, ***Senior Consultant Nephrology, Department of Nephrology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Sanjiv Jasuja, Senior Consultant Nephrology, Department of Nephrology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects ~40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 μg/min and d”199 μg/min) and macroalbuminuria (UAE e”200 μg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dL) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes. Keywords: Diabetic nephropathy, Microalbuminuria, ACE inhibitors, ARBS
Clinical definition It is a clinical syndrome characterized by persistent albuminuria, a relentless decline in GFR, raised arterial BP and enhanced cardiovascular morbidity and mortality. Albuminuria being the first sign and peripheral edema is first symptom. There is relentless, often linear but highly variable rate of decline of GFR ranging from 2-20 mL/min/ yr with mean 12 mL/min/yr. Microalbuminuria Strongly predicts the development of diabetic nephropathy. It is defined as urinary albumin excretion between 30-300 mg/24 hour (or 20-200mgm/min) irrespective of how the urine is collected. Urinary albumin excretion within microalbuminuric range in at least 2 out of 3 non-ketotic, sterile samples is generally accepted definition of persistent micro-albuminuria Risk factors Genetic susceptibility - The likelihood of developing diabetic nephropathy is markedly increased if parents have 105
the same. These observations have been made in both type I and 2 DM. One report evaluated on Pima Indian families in which 2 successive generation had type 2 DM, likelihood of offsprings developing overt proteinurea was 14% if neither parents had proteinurea, 23% if one had and 46% if both parents had proteinurea. This increased risk can not be explained by the duration of DM, hypertension or degree of glycemic control. Possible genetic loci are ACE gene polymorphism, Angiotensin II type 2 Receptor on X chromosome, Aldolase reductase gene. Other risk factors are Age, Hypertension, Race, Obesity, Smoking and OC pills. SCREENING FOR DIABETIC NEPHROPATHY It involves the early detection of proteinuria and kidney failure. Most commonly, proteinuria is detected using a standard urine dipstick. However, this method is extremely insensitive and may be negative even with protein excretion rates 10 times the normal value. Twenty four hour or other timed urine collections for measurement of protein or albumin are particularly unreliable in diabetic patients, who often have autonomic Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
neuropathy and incomplete bladder emptying. Thus the most reliable and reproducible measurement of proteinuria is the protein to creatinine ratio in a spot urine sample and it is recommended by the National Kidney Foundation as the standard measurement of proteinuria in patients with diabetes. Repeated measurements of the urine albumin to creatinine ratio may be used to monitor the effectiveness of therapy [1]. The American Diabetes Association (ADA) recommends that screening for proteinuria be performed when type 2 diabetes is first diagnosed and 5 years after the diagnosis of type 1 diabetes. The plasma creatinine, measured urinary clearance of creatinine, and estimated creatinine clearance are all used to approximate kidney function in patients. The plasma creatinine rises above normal levels only when >50% of kidney function is lost, making it relatively insensitive marker for early renal failure [2]. In addition, plasma creatinine is dependent on muscle mass and can be misleading in certain cases. Estimation of creatinine clearance (using Cockcroft and Gault formula) has been recommended as the most reliable practical measure of kidney function. PRIMARY PREVENTION
SECONDARY PREVENTION This includes the treatment strategies for the prevention of progression from the microalbuminuria to the albuminuria stage. Glycemic control Strict control of plasma glucose concentration can stabilize or reduce the degree of proteinuria in type 1 diabetics versus a common increase in proteinuria in conventionally treated patients; however this difference may not be apparent until two years of relative normoglycemia. The importance of of glycemic control in secondary prevention was also demonstrated in the DCCT. Among patients with microalbuminuria at entry, albumin excretion increased at an average of 6.5% per year in patients receiving conventional insulin therapy versus no change in those treated with intensive insulin [3]. Anti-hypertensive therapy
Primary prevention includes the treatment modalities to prevent the development of nephropathy in a patient with no evidence of kidney injury (normoalbuminuria and normal renal function). Strict glycemic control and antihypertensive agents are the two most readily applicable treatment strategies [2-4]. Blood glucose control In the DCCT trial, after 6.5 years of follow up, the prevalence of new microalbuminuria was much lower with intensive therapy-16% versus 27%. Previous intensive treatment with near normal glycemia during the DCCT had an extended benefit in delaying the onset and progression of diabetic nephropathy [3]. The beneficial effect of strict glycemic control in type 2 diabetics has been demonstrated in the UKPDS, in which a 0.9% reduction in HbA1c was associated with a 34% reduction in the development of albuminuria over 12 years[4]. Anti hypertensive therapy It has been demonstrated that antihypertensive therapy slows the development of diabetic nephropathy and ACE inhibitors have been found superior in this regard [1]. The enhanced efficacy of ACE inhibition in this setting may be related to activation of intrarenal renin angiotensin system. Several clinical trials in normotensive diabetic patients comparing ACE inhibitors to placebo and in hypertensive diabetic patients comparing ACE inhibitors Apollo Medicine, Vol. 6, No. 2, June 2009
to other antihypertensives have shown similar beneficial effects of ACE inhibition in preventing diabetic nephropathy.
In patients with microalbuminuria, progression to overt proteinuria can be reduced by aggressive blood pressure control, especially with an ACE inhibitor which may be beneficial even in normotensive patients. Angiotensin receptor blockers (ARBs) appear to have the same benefits as ACE inhibitors in type 2 hypertensive patients with microalbuminuria. In a study of 590 such patients randomized to either irbesartan or placebo, the development of overt nephropathy was significantly more common in the placebo group (14.9% versus 9.7% and 5.2% with 150 and 300 mg of irbesartan). Microalbuminuria may actually regress in some type 1 diabetic patients, particularly those with good glycemic control, low blood pressure and cholesterol levels, and microalbuminuria of short duration. In type 2 diabetics, the efficacy of intensive combined therapy (consisting of strict glycemic and blood pressure control, ACE inhibitor, advice concerning diet, exercise and smoking cessation) in prevention and progression of nephropathy was demonstrated in the Steno type 2 trial [5]. STRATEGIES FOR RETARDING PROGRESSION OF DIABETIC NEPHROPATHY Glycemic control It has been suggested that, in contrast to the benefit seen in early diabetic kidney disease, strict glycemic control does not slow the rate of progressive renal injury
106
Review Article
once overt proteinuria has developed [2]. However results from pancreatic transplant recipients in which true euglycemia is restored suggest that this may not be correct. In a study of thirteen type 1 diabetic patients with pancreatic transplant, stabilization of histological changes of diabetic nephropathy was seen, at 5 years of follow up. Subsequent follow up of 8 of these patients at10 years demonstrated reversal of histological lesions. Anti-hypertensive therapy The target blood pressure level for diabetic patients in general is <130/80 mmHg. The target is even more stringent, <120/75 mmHg, for patients with >1g proteinuria [6]. A single antihypertensive agent is usually inadequate in achieving blood pressure goals and a combination of antihypertensive agents is usually required. Blockade of the renin angiotensin system with either ACE inhibitors or angiotensin II receptor blockers is the first line of therapy. So far, there is little evidence in type 1 diabetes that angiotensin II receptor blockers prevent or slow the course of kidney failure; however they have been shown to reduce proteinuria, in short term studies. In contrast, because of two recent studies of angiotensin II receptor blockade in type 2 diabetic patients with nephropathy; these agents are now suggested as firstline therapy in these patients. Both these randomized controlled trials, each with more than 1500 patients showed reductions of ~30% in ESRD over 3 years. The non dihydropyridine CCBs – verapamil and diltiazem have also been demonstrated to have antiproteinuric effect [6]. The superiority of combination therapy with ACE inhibitor and ARB compared to either therapy alone in decreasing proteinurea has been established in both type I and type 2diabetes. However there is no clear evidence that combinations therapy slows progression of diabetic nephropathy [1]. In addition combination therapy is associated higher incidence adverse side effects. AVOID trial compared aliskiren (first oral renin inhibitor) plus losartan, to losartan alone, concluded that the combination was associated with 20% greater reduction in proteinurea, but the role of aliskiren preventing progression of CKD is not yet known.Aldosterone antagonist appears to reduce proteinurea when used alone and have additive effect on proteinurea when used in combination with ARB or ACE inhibitors. But there is no long-term data regarding benefit of this combination on slowing rate of progression of nephropathy. The risk of aggravating hyperkalemia further limits use of combination therapy. However this combination may be indicated in therapy of heart failure. Dietary protein restriction Dietary protein restriction is another modality that may slow the long term decline in GFR in diabetic
nephropathy. One of the problems associated with a low protein diet is that it can lead to protein malnutrition. Treatment of hyperlipidemia Aggressive lipid lowering is an important part of the medical management of all diabetic patients as hyperlipidemia is an important risk factor for atherosclerosis. Lipid lowering may decrease the rate of progression of diabetic nephropathy. However, several studies have failed to demonstrate significant beneficial effects of lipid lowering therapy on proteinuria or decline of renal function, despite adequate reductions in serum lipid levels. Smoking cessation Smoking has been a significant risk factor for the development of microalbuminuria and overt proteinuria. Smokers and ex-smokers had earlier onset of proteinuria and a higher prevalence of uremic symptoms than nonsmoking controls [5]. Thus, smoking cessation should be strongly advocated as a means of retarding progression of diabetic nephropathy. Weight reduction Marked decreases in proteinuria may be observed in obese diabetics who lose weight. This was demonstrated in a randomized trial of 30 overweight patients with proteinuric nephropathy, a mean weight loss of 4% was associated with significant decrease in proteinuria. MANAGEMENT OF DIABETIC NEPHROPATHY The following recommendations for therapeutic goals are consistent with KDOQI [Kidney diseases outcomes and quality initiatives] guidelines. Reductions of protein excretion to less than 500 to 1000 mg/day or minimum reduction of 60% of baseline values [1]. It is also recommended that strict glycemic control should be achieved and HBA1c levels should be targeted below 7%. Reduction of BP to less than 130/80 mmHg, diastolic BP should not be lowered below 75 mmHg in patients with coronary artery disease and systolic BP not below 110 mmHg in any patient [7]. Goal of diuretic therapy is to attain dry weight (defined by weight at which further fluid loss leads to symptoms). If appropriate diuretics therapy plus either ARB or ACE inhibitor does not achieve target BP, non dihydropyridine CCB is indicated [6]. However it should not be given in combination with beta-blocker. Thus in patients already being treated with beta blockers for another indication, a long acting dihydropyridine CCB may be added.
107
Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
MANAGEMENT IN ESRD POPULATION Although the development and progression of diabetic nephropathy may be retarded, it is a relentless progressive disease which invariably reaches ESRD in many patients. KDOQI guidelines suggest RRT in diabetic nephropathy with GFR <15 mL/min as compared to <10 mL/min in non diabetic patients. AV fistula should be considered in all patients with GFR <25mL/min. Patient survival in diabetes on maintenance dialysis is lower than that seen in non diabetics. In 2006 USRDS database, only 25% of diabetics survived 5 years after initiation of dialysis. Cardiovascular disease is most common cause of death accounting for greater than 50% of cases. Strict glycemic control should be achieved to prevent the risk of infections and extra-renal complications.
either modality was observed among young diabetics with baseline co morbidities. REFERENCES
Dialysis versus renal transplantation According to USRDS reports patients’ survival at 5 years after transplantation ranged from 75% to 83%. Transplantation is associated with better quality of life and higher degree of rehabilitation. Hemodialysis versus peritoneal dialysis Relative effect of hemodialysis and CAPD on survival of diabetic patients is uncertain. Initial reports suggest CAPD was associated with better outcome. In contrast data from USRDS suggested mortality may actually be increased in diabetics on CAPD. Another study revealed mortality risk was significantly higher on hemodialysis than CAPD among younger diabetes with no co morbidity. By comparison HD was associated with lower mortality risk in older diabetics with either no co morbidities or baseline co morbidity. No difference in survival with
Apollo Medicine, Vol. 6, No. 2, June 2009
108
1. Mogenson CE, Neldam S, Tikkanen I, et al. Randomized controlled trial of dual blockade of rennin angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 32: 1440-1444. 2. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347: 797. 3. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression if diabetic nephropathy: the epidemiology of diabetes interventions and complications (EDIC) study. JAMA 2003; 290: 2159. 4. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the diabetes control and complications trial. Kidney Int 1995; 47:1703-1720. 5. Chuahirun T, Wesson DE. Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition. Am J Kidney Dis 2002; 39: 376-382. 6. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837. 7. Brenner BM, Cooper M, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869.
DIABETIC NEPHROPATHY: PREVENTION AND MANAGEMENT Sai Prasad Sahoo*, Sandeep Mandal** and Sanjiv Jasuja*** *Registrar, **Clinical Associate, ***Senior Consultant Nephrology, Department of Nephrology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Sanjiv Jasuja, Senior Consultant Nephrology, Department of Nephrology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects ~40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 μg/min and d”199 μg/min) and macroalbuminuria (UAE e”200 μg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dL) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes. Keywords: Diabetic nephropathy, Microalbuminuria, ACE inhibitors, ARBS
Clinical definition It is a clinical syndrome characterized by persistent albuminuria, a relentless decline in GFR, raised arterial BP and enhanced cardiovascular morbidity and mortality. Albuminuria being the first sign and peripheral edema is first symptom. There is relentless, often linear but highly variable rate of decline of GFR ranging from 2-20 mL/min/ yr with mean 12 mL/min/yr. Microalbuminuria Strongly predicts the development of diabetic nephropathy. It is defined as urinary albumin excretion between 30-300 mg/24 hour (or 20-200mgm/min) irrespective of how the urine is collected. Urinary albumin excretion within microalbuminuric range in at least 2 out of 3 non-ketotic, sterile samples is generally accepted definition of persistent micro-albuminuria Risk factors Genetic susceptibility - The likelihood of developing diabetic nephropathy is markedly increased if parents have 105
the same. These observations have been made in both type I and 2 DM. One report evaluated on Pima Indian families in which 2 successive generation had type 2 DM, likelihood of offsprings developing overt proteinurea was 14% if neither parents had proteinurea, 23% if one had and 46% if both parents had proteinurea. This increased risk can not be explained by the duration of DM, hypertension or degree of glycemic control. Possible genetic loci are ACE gene polymorphism, Angiotensin II type 2 Receptor on X chromosome, Aldolase reductase gene. Other risk factors are Age, Hypertension, Race, Obesity, Smoking and OC pills. SCREENING FOR DIABETIC NEPHROPATHY It involves the early detection of proteinuria and kidney failure. Most commonly, proteinuria is detected using a standard urine dipstick. However, this method is extremely insensitive and may be negative even with protein excretion rates 10 times the normal value. Twenty four hour or other timed urine collections for measurement of protein or albumin are particularly unreliable in diabetic patients, who often have autonomic Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
neuropathy and incomplete bladder emptying. Thus the most reliable and reproducible measurement of proteinuria is the protein to creatinine ratio in a spot urine sample and it is recommended by the National Kidney Foundation as the standard measurement of proteinuria in patients with diabetes. Repeated measurements of the urine albumin to creatinine ratio may be used to monitor the effectiveness of therapy [1]. The American Diabetes Association (ADA) recommends that screening for proteinuria be performed when type 2 diabetes is first diagnosed and 5 years after the diagnosis of type 1 diabetes. The plasma creatinine, measured urinary clearance of creatinine, and estimated creatinine clearance are all used to approximate kidney function in patients. The plasma creatinine rises above normal levels only when >50% of kidney function is lost, making it relatively insensitive marker for early renal failure [2]. In addition, plasma creatinine is dependent on muscle mass and can be misleading in certain cases. Estimation of creatinine clearance (using Cockcroft and Gault formula) has been recommended as the most reliable practical measure of kidney function. PRIMARY PREVENTION
SECONDARY PREVENTION This includes the treatment strategies for the prevention of progression from the microalbuminuria to the albuminuria stage. Glycemic control Strict control of plasma glucose concentration can stabilize or reduce the degree of proteinuria in type 1 diabetics versus a common increase in proteinuria in conventionally treated patients; however this difference may not be apparent until two years of relative normoglycemia. The importance of of glycemic control in secondary prevention was also demonstrated in the DCCT. Among patients with microalbuminuria at entry, albumin excretion increased at an average of 6.5% per year in patients receiving conventional insulin therapy versus no change in those treated with intensive insulin [3]. Anti-hypertensive therapy
Primary prevention includes the treatment modalities to prevent the development of nephropathy in a patient with no evidence of kidney injury (normoalbuminuria and normal renal function). Strict glycemic control and antihypertensive agents are the two most readily applicable treatment strategies [2-4]. Blood glucose control In the DCCT trial, after 6.5 years of follow up, the prevalence of new microalbuminuria was much lower with intensive therapy-16% versus 27%. Previous intensive treatment with near normal glycemia during the DCCT had an extended benefit in delaying the onset and progression of diabetic nephropathy [3]. The beneficial effect of strict glycemic control in type 2 diabetics has been demonstrated in the UKPDS, in which a 0.9% reduction in HbA1c was associated with a 34% reduction in the development of albuminuria over 12 years[4]. Anti hypertensive therapy It has been demonstrated that antihypertensive therapy slows the development of diabetic nephropathy and ACE inhibitors have been found superior in this regard [1]. The enhanced efficacy of ACE inhibition in this setting may be related to activation of intrarenal renin angiotensin system. Several clinical trials in normotensive diabetic patients comparing ACE inhibitors to placebo and in hypertensive diabetic patients comparing ACE inhibitors Apollo Medicine, Vol. 6, No. 2, June 2009
to other antihypertensives have shown similar beneficial effects of ACE inhibition in preventing diabetic nephropathy.
In patients with microalbuminuria, progression to overt proteinuria can be reduced by aggressive blood pressure control, especially with an ACE inhibitor which may be beneficial even in normotensive patients. Angiotensin receptor blockers (ARBs) appear to have the same benefits as ACE inhibitors in type 2 hypertensive patients with microalbuminuria. In a study of 590 such patients randomized to either irbesartan or placebo, the development of overt nephropathy was significantly more common in the placebo group (14.9% versus 9.7% and 5.2% with 150 and 300 mg of irbesartan). Microalbuminuria may actually regress in some type 1 diabetic patients, particularly those with good glycemic control, low blood pressure and cholesterol levels, and microalbuminuria of short duration. In type 2 diabetics, the efficacy of intensive combined therapy (consisting of strict glycemic and blood pressure control, ACE inhibitor, advice concerning diet, exercise and smoking cessation) in prevention and progression of nephropathy was demonstrated in the Steno type 2 trial [5]. STRATEGIES FOR RETARDING PROGRESSION OF DIABETIC NEPHROPATHY Glycemic control It has been suggested that, in contrast to the benefit seen in early diabetic kidney disease, strict glycemic control does not slow the rate of progressive renal injury
106
Review Article
once overt proteinuria has developed [2]. However results from pancreatic transplant recipients in which true euglycemia is restored suggest that this may not be correct. In a study of thirteen type 1 diabetic patients with pancreatic transplant, stabilization of histological changes of diabetic nephropathy was seen, at 5 years of follow up. Subsequent follow up of 8 of these patients at10 years demonstrated reversal of histological lesions. Anti-hypertensive therapy The target blood pressure level for diabetic patients in general is <130/80 mmHg. The target is even more stringent, <120/75 mmHg, for patients with >1g proteinuria [6]. A single antihypertensive agent is usually inadequate in achieving blood pressure goals and a combination of antihypertensive agents is usually required. Blockade of the renin angiotensin system with either ACE inhibitors or angiotensin II receptor blockers is the first line of therapy. So far, there is little evidence in type 1 diabetes that angiotensin II receptor blockers prevent or slow the course of kidney failure; however they have been shown to reduce proteinuria, in short term studies. In contrast, because of two recent studies of angiotensin II receptor blockade in type 2 diabetic patients with nephropathy; these agents are now suggested as firstline therapy in these patients. Both these randomized controlled trials, each with more than 1500 patients showed reductions of ~30% in ESRD over 3 years. The non dihydropyridine CCBs – verapamil and diltiazem have also been demonstrated to have antiproteinuric effect [6]. The superiority of combination therapy with ACE inhibitor and ARB compared to either therapy alone in decreasing proteinurea has been established in both type I and type 2diabetes. However there is no clear evidence that combinations therapy slows progression of diabetic nephropathy [1]. In addition combination therapy is associated higher incidence adverse side effects. AVOID trial compared aliskiren (first oral renin inhibitor) plus losartan, to losartan alone, concluded that the combination was associated with 20% greater reduction in proteinurea, but the role of aliskiren preventing progression of CKD is not yet known.Aldosterone antagonist appears to reduce proteinurea when used alone and have additive effect on proteinurea when used in combination with ARB or ACE inhibitors. But there is no long-term data regarding benefit of this combination on slowing rate of progression of nephropathy. The risk of aggravating hyperkalemia further limits use of combination therapy. However this combination may be indicated in therapy of heart failure. Dietary protein restriction Dietary protein restriction is another modality that may slow the long term decline in GFR in diabetic
nephropathy. One of the problems associated with a low protein diet is that it can lead to protein malnutrition. Treatment of hyperlipidemia Aggressive lipid lowering is an important part of the medical management of all diabetic patients as hyperlipidemia is an important risk factor for atherosclerosis. Lipid lowering may decrease the rate of progression of diabetic nephropathy. However, several studies have failed to demonstrate significant beneficial effects of lipid lowering therapy on proteinuria or decline of renal function, despite adequate reductions in serum lipid levels. Smoking cessation Smoking has been a significant risk factor for the development of microalbuminuria and overt proteinuria. Smokers and ex-smokers had earlier onset of proteinuria and a higher prevalence of uremic symptoms than nonsmoking controls [5]. Thus, smoking cessation should be strongly advocated as a means of retarding progression of diabetic nephropathy. Weight reduction Marked decreases in proteinuria may be observed in obese diabetics who lose weight. This was demonstrated in a randomized trial of 30 overweight patients with proteinuric nephropathy, a mean weight loss of 4% was associated with significant decrease in proteinuria. MANAGEMENT OF DIABETIC NEPHROPATHY The following recommendations for therapeutic goals are consistent with KDOQI [Kidney diseases outcomes and quality initiatives] guidelines. Reductions of protein excretion to less than 500 to 1000 mg/day or minimum reduction of 60% of baseline values [1]. It is also recommended that strict glycemic control should be achieved and HBA1c levels should be targeted below 7%. Reduction of BP to less than 130/80 mmHg, diastolic BP should not be lowered below 75 mmHg in patients with coronary artery disease and systolic BP not below 110 mmHg in any patient [7]. Goal of diuretic therapy is to attain dry weight (defined by weight at which further fluid loss leads to symptoms). If appropriate diuretics therapy plus either ARB or ACE inhibitor does not achieve target BP, non dihydropyridine CCB is indicated [6]. However it should not be given in combination with beta-blocker. Thus in patients already being treated with beta blockers for another indication, a long acting dihydropyridine CCB may be added.
107
Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
MANAGEMENT IN ESRD POPULATION Although the development and progression of diabetic nephropathy may be retarded, it is a relentless progressive disease which invariably reaches ESRD in many patients. KDOQI guidelines suggest RRT in diabetic nephropathy with GFR <15 mL/min as compared to <10 mL/min in non diabetic patients. AV fistula should be considered in all patients with GFR <25mL/min. Patient survival in diabetes on maintenance dialysis is lower than that seen in non diabetics. In 2006 USRDS database, only 25% of diabetics survived 5 years after initiation of dialysis. Cardiovascular disease is most common cause of death accounting for greater than 50% of cases. Strict glycemic control should be achieved to prevent the risk of infections and extra-renal complications.
either modality was observed among young diabetics with baseline co morbidities. REFERENCES
Dialysis versus renal transplantation According to USRDS reports patients’ survival at 5 years after transplantation ranged from 75% to 83%. Transplantation is associated with better quality of life and higher degree of rehabilitation. Hemodialysis versus peritoneal dialysis Relative effect of hemodialysis and CAPD on survival of diabetic patients is uncertain. Initial reports suggest CAPD was associated with better outcome. In contrast data from USRDS suggested mortality may actually be increased in diabetics on CAPD. Another study revealed mortality risk was significantly higher on hemodialysis than CAPD among younger diabetes with no co morbidity. By comparison HD was associated with lower mortality risk in older diabetics with either no co morbidities or baseline co morbidity. No difference in survival with
Apollo Medicine, Vol. 6, No. 2, June 2009
108
1. Mogenson CE, Neldam S, Tikkanen I, et al. Randomized controlled trial of dual blockade of rennin angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 32: 1440-1444. 2. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347: 797. 3. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression if diabetic nephropathy: the epidemiology of diabetes interventions and complications (EDIC) study. JAMA 2003; 290: 2159. 4. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the diabetes control and complications trial. Kidney Int 1995; 47:1703-1720. 5. Chuahirun T, Wesson DE. Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition. Am J Kidney Dis 2002; 39: 376-382. 6. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837. 7. Brenner BM, Cooper M, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869.